Targeting breast cancer stem cells

 描述（由申请人提供）：肿瘤细胞异质性对有效癌症治疗的开发提出了巨大的挑战。除了经过充分研究的突变和克隆选择导致的遗传异质性之外，越来越多的证据表明表观遗传异质性在介导治疗耐药性中发挥着重要作用。调节细胞分化的表观遗传机制在肿瘤内产生分层组织的细胞克隆。这些层次结构的顶端是驱动肿瘤生长和转移的癌症干细胞（CSC）。 CSC 被赋予表型可塑性，使其能够在间充质状态和上皮样状态之间转变，这一过程受肿瘤微环境的调节。 CSC 还表现出对细胞毒性药物和放射治疗的内在抵抗力，并且还可能对针对大量肿瘤群体的分子靶向治疗产生抵抗力。 CSC 的异质性、可塑性和治疗耐药性对于有效癌症疗法的开发具有深远的影响。 在过去的十年中，我们的实验室已经确定了乳腺癌以及其他肿瘤类型中 CSC 的标记，并开发了有助于这些细胞的分离和表征的体外模型和小鼠模型。我们已经确定了许多细胞内在和微环境驱动的途径，这些途径可以调节这些细胞，促进 CSC 靶向药物的开发，其中一些药物现已进入临床试验。我们建议通过应用单细胞基因组和蛋白质组技术来扩展这些研究，以单细胞分辨率表征 CSC 异质性。我们将开发新技术，以捕获和分子分析分子注释 PDX 模型以及原发患者血液样本中的循环 CSC。这些技术将有助于更精确地选择针对 CSC 的药物，并有助于实时评估针对 CTC 的临床试验患者的治疗效果。成功靶向 CSC 有可能显着改善乳腺癌以及其他恶性肿瘤患者的预后。

 DESCRIPTION (provided by applicant): Tumor cellular heterogeneity presents a formidable challenge to the development of effective cancer therapeutics. In addition to well-studied genetic heterogeneity resulting from mutation and clonal selection, there is mounting evidence for a fundamental role of epigenetic heterogeneity in mediating therapeutic resistance. Epigenetic mechanisms regulating cellular differentiation generate hierarchically organized cellular clones within tumors. At the apex of these hierarchies are cancer stem cells (CSCs) which drive tumor growth and metastasis. CSCs are endowed with phenotypic plasticity enabling them to transition between mesenchymal and epithelial-like states, processes regulated by the tumor microenvironment. CSCs also display intrinsic resistance to cytotoxic agents and radiation therapy and also may be resistant to molecularly targeted therapies aimed at bulk tumor populations. CSC heterogeneity, plasticity, and therapeutic resistance have profound implications for development of effective cancer therapies. Over the past decade, our laboratory has identified markers for CSCs in breast cancer, as well as other tumor types and developed in vitro and mouse models that have facilitated isolation and characterization of these cells. We have identified a number of cell intrinsic and microenvironmentally driven pathways that regulate these cells facilitating development of CSC-targeting drugs, a number of which have now entered clinical trials. We propose to extend these studies by applying single-cell genomic and proteomic technologies to characterize CSC heterogeneity at single-cell resolution. We will develop novel technologies to capture and molecularly interrogate circulating CSCs in molecularly annotated PDX models, as well as in primary patient blood samples. These technologies will facilitate more precise selection of agents to target CSCs, as well as facilitating real time assessment of therapeutic efficacy for patients on CTC targeting clinical trials. The successful targeting of CSCs has the potential to significantly improve the outcomes of patients with breast cancer, as well as other malignancies.